17-(pyridineacrylyl)-4-androsten-3-ones



United States Patent 2,862,923 17-(PYRIDINEACRYLYL)-4-ANDROSTEN-3-0NESRaymond M. Dodson, Park Ridge,-lll., assignor to G. D. Searle & Co.,Chicago, 111., a corporation of Delaware No Drawing. ApplicationApril 2,1956 Serial No. 575,333

-4-Claims. (CL 260-4395,)

The present invention relates to a new group of heterocyclic derivativesof steroids and, more specifically, to 17-(pyridineacrylyl)-4-androsten-3-oneswhich can be represented by thegeneral structural formula The compounds of this invention are of valuebecause of their hormonal etlecttand particularly theirantihyp'ertensive and luteoid action.

As described in my copending application, Serial No.

472,775, filed December 2, 1954, now U. S. Patent No. 2,753,341, ofwhich the present application is a continuation-in-part the compounds ofthis invention are conveniently prepared by Oppenauer oxidation of thecorresponding 17 -pyridineacrylyl-S-androsten-3-ols. The 4-androsten-3-ones of this invention differ in their physiologicalproperties from the S-androsten-S-ols from which they are derived inthat they lack the effects of the latter on the heart muscle.

1 The pyridine derivatives of this invention form salts with inorganicand strong organic acids including hydrochloric, hydrobromic, hydriodic,sulfuric, phosphoric, sulfamic, acetic, propionic, butyric, benzoic,cinnamic, citric, lactic, ascorbic, gluconi, and related acids.

The compounds which constitute this invention and the methods for theirpreparation will appear more fully from the consideration of thefollowing examples. However, these are not to be construed as limitingthe invention in spirit or in scope. Quantities of materials areindicated in parts by weight and temperatures in degrees centigrade.

Example 1 In 100 parts of methanol there are dissolved first 2.3 partsof sodium, then, with heating, 6.32 parts of S-hydroxy-S-pregnen-ZO-oneand finally, 4.28 parts of isonicotinaldehyde. The reaction mixture ispermitted to stand at room temperature for a week after which theprecipitate is collected on a filter, and washed with cold methanol. Theproduct thus obtained is recrystallized from acetone to yield al7-(4-pyridineacrylyl)-5-androsten-3-ol which melts at about 229.5-23l.5C.

To an anhydrous mixture of 2 parts of this compound, 30 parts of tolueneand 20 parts of cyclohexanone are added 2.5 parts of aluminumisopropoxide in 10 parts of toluene. Theresultingmix ture is heated for20 minutes under refluxand then poured into parts of a saturated aqueousRochelle saltso'lution. After removal of the organic solvents bysteamdistillation, the residue is collected on a filter and applied in a50% solution of benzene in petroleum ether to a chromatography columncontaining parts of alumina. The column is washed with mixtures ofpetroleum ether and benzene containing increasing concentrations ofbenzene, with pure benzene and is then developed with benzene "solutionscontaining increasing concentrations of ethyl acetate in benzene.Elution with a ..5% solution of ethyl acetate in benzene and triturationof the eluate with ether yields a precipitate whichzisirecrystallizedsuccessively from ether, dilute methanol and ether to yield :17-(dmyridtneaerylyle- 4fandros'ten-fione.melting at about 1-52; 4 15 5 C."The specific :optical rotation, as determined in a chloroform solution,-.is 'll'a] =+224".. TEhe ultraviolet absorption spectrum shows amaximum :at.247.5 millimic'r'o'ns with a-molecular extinction=coeflici'e'nt of "about 26,400. The product has the structural formula5 Example 2 To a solution of 2.3 parts of sodium in 100 parts ofmethanol, there are added 6.32 parts of 3-hydroxy-5- pregnen-ZO-one andthen 4.28 parts of nicotinaldehyde. After standing at room temperaturefor 15 hours the mixture is filtered and the material collected on thefilter is Washed with methanol. On crystallization from ethanol, thel7-(3-pyridineacrylyl)-5-androsten-3-ol thus obtained melts at about193-195 C.

To an anhydrous mixture of 2 parts of17-(3-pyridineacrylyl)-5-androsten-3-ol in 30 parts of toluene and 20parts of cyclohexanone are added 2.5 parts of aluminum isopropoxide in10 parts of toluene. The mixture is heated at reflux for 20 minutes,poured into 100 parts of a saturated aqueous Rochelle salt solution andthen steam distilled to remove the organic solvents. The solid residueis collected on a filter and crystallized successively first from dilutemethanol, then from acetone and petroleum ether, and then again frommethanol to yield 17-(3-pyridineacrylyl)-4-androsten-3-one melting atabout 253-255 C. The specific optical rotation in chloroform is [a]=+l91.l.

The mother liquors from the above crystallizations are combined,evaporated to a small volume and applied in a 42% solution of benzene inpetroleum ether to a. chromatography column containing 150 parts ofalumina. The column is developed with petroleum ether solutionscontaining 46, 50, 60, 70, 80, and 90% of benzene, With benzene, and a2% solution of ethyl acetate in benzene. Elution with a 5% solution ofethyl acetate in benzene and concentration of the eluate yields aresidue which is crystallized successively from a mixture of petroleumether and acetone, dilute methanol and a mixture of acetone andcyclohexane. The resulting isomeric form of 17 (3pyridineacrylyl)-4-androsten-3-one melts at 3 about 188-1895 C. and hasa specific rotation of [a] =+217 in chloroform. Both isomers thus formedhave the structural formula Example 3 .melt at about 214-215.5 C.

To a solution of one part of the l7-(2-pyridineacrylyl)- -androsten-3-olthus obtained in parts of toluene and 10 parts of cyclohexanone areadded 1.25 parts of aluminum isopropoxide in 5 parts of toluene. Afterheating under reflux for minutes, the mixture is poured into 100 partsof saturated Rochelle salt solution. The organic solvents are removed bysteam distillation and the solid residue is collected on a filter. Uponrepeated recrystallization from dilute methanol the17-(2-pyridiueacrylyl)-4-androsten-3-one thus obtained melts at about232234 C. A chloroform solution shows a specific rotation of [oz] =+192.The ultraviolet absorption spectrum shows maxima at about 246 and 292millimicrons with molecular extinction coeflicients of about 24,-

The compound has the CH=OH o N What is claimed is: 1. A compound of thestructural formula ZH=0H O CH3 N/ 2.l7-(4-pyridineacrylyl)-4-androsten-3-one. 3.17-'(3-pyridineacrylyl)-4-androsten-3-one. 4.17-(2-pyridineacrylyl)-4-androsten-3-one.

References Cited in the file of this patent UNITED STATES PATENTS2,665,274 Conbere Jan. 5, 1954 2,750,380 Dodson June 12, 1956 2,753,341Dodson July 3, 1956 OTHER REFERENCES King: IACS; vol. 66, page 1612(1944)-

1. A COMPOUND OF THE STRUCTURAL FORMULA